Format

Send to

Choose Destination
Int J Parasitol Drugs Drug Resist. 2019 Apr;9:59-71. doi: 10.1016/j.ijpddr.2018.12.007. Epub 2018 Dec 30.

Tetrahydroquinoxalines induce a lethal evisceration phenotype in Haemonchus contortus in vitro.

Author information

1
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, Australia.
2
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, Australia; Faculty of Science and Technology, Federation University, Ballarat, Victoria, Australia.
3
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. Electronic address: jonathan.baell@monash.edu.
4
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
5
Centre for Advanced Histology and Microscopy, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
6
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, Australia; Yourgene Bioscience, Taipei, Taiwan.
7
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
8
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: jabbara@unimelb.edu.au.
9
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: robinbg@unimelb.edu.au.

Abstract

In the present study, the anthelmintic activity of a human tyrosine kinase inhibitor, AG-1295, and 14 related tetrahydroquinoxaline analogues against Haemonchus contortus was explored. These compounds were screened against parasitic larvae - exsheathed third-stage (xL3) and fourth-stage (L4) - using a whole-organism screening assay. All compounds were shown to have inhibitory effects on larval motility, development and growth, and induced evisceration through the excretory pore in xL3s. The estimated IC50 values ranged from 3.5 to 52.0 μM for inhibition of larval motility or development. Cytotoxicity IC50 against human MCF10A cells was generally higher than 50 μM. Microscopic studies revealed that this eviscerated (Evi) phenotype occurs rapidly (<20 min) and relates to a protrusion of internal tissues and organs (evisceration) through the excretory pore in xL3s; severe pathological damage in L4s as well as a suppression of larval growth in both stages were also observed. Using a relatively low concentration (12.5 μM) of compound m10, it was established that the inhibitor has to be present for a relatively short time (between 30 h and 42 h) during in vitro development from xL3 to L4, to induce the Evi phenotype. Increasing external osmotic pressure prevented evisceration and moulting, and xL3s remained unaffected by the test compound. These results point to a mode of action involving a dysregulation of morphogenetic processes during a critical time-frame, in agreement with the expected behaviour of a tyrosine kinase inhibitor, and suggest potential for development of this compound class as nematocidal drugs.

KEYWORDS:

Anthelmintic; Evisceration (Evi) phenotype; Haemonchus; Moulting; Quinoxalines; Whole-organism screening

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center